Water-soluble iron-carbohydrate complexes, production thereof, and medicaments containing said complexes

ABSTRACT

Water soluble iron carbohydrate complex obtainable from an aqueous solution of iron (III) salt and an aqueous solution of the oxidation product of one or more maltrodextrins using an aqueous hypochlorite solution at a pH-value within the alkaline range, where, when one maltodextrin is applied, its dextrose equivalent lies between 5 and 20, and when a mixture of several maltodextrins is applied, the dextrose equivalent of the mixture lies between 5 and 20 and the dextrose equivalent of each individual maltodextrin contained in the mixture lies between 2 and 40, process for its production and medicament for the treatment and prophylaxis of iron deficiency conditions.

This application is a 35 U.S.C. section 371 filing of PCT/EP2003/011596,filed on Oct. 20, 2003, and published May 6, 2004 as WO 2004/037865 A1,which claims priority to German Patent Application DE 10249552.1, filedOct. 23, 2002. The foregoing documents are incorporated herein byreference.

The present invention concerns water-soluble iron carbohydrate complexeswhich are used for the treatment of iron deficiency anaemia, theirpreparation, medicaments containing them and their use for theprophylaxis or treatment of iron deficiency anaemia. The medicaments areespecially useful for parenteral application.

Iron deficiency anaemia can be treated or prophylactically treated bythe application of medicaments containing iron. In this respect the useof iron carbohydrate complexes is known. A water soluble iron (III)hydroxide sucrose complex is a frequently and successfully usedpreparation (Danielson, Salmonson, Derendorf, Geisser, Drug Res., Vol.46: 615-621, 1996). It is also known in the art to use, for parenteralapplication, iron dextran complexes as well as complexes based onpullulans (WO 02/46241), which are difficult to obtain and have to beproduced under pressure at high temperatures and involving hydrogenatingsteps. Other iron carbohydrate complexes are also known for oralapplication.

The problem to be solved by the present invention is to provide an ironpreparation which is especially to be applied parenterally and which caneasily be sterilized; the known parenterally applicable preparations onthe basis of sucrose and dextran were only stable at temperatures up to100° C., which made sterilisation difficult. Further, the preparation tobe provided by the invention shall have reduced toxicity and shall avoiddangerous anaphylactic shocks which can be induced by dextran. Also, thestability of the complexes of the preparation shall be high in order toenable a high applicable dosage and a high rate of application.Furthermore, the iron preparation is to be producible from easilyobtainable starting products and without great effort.

In accordance with the present invention the problem can be solved byproviding iron (III) carbohydrate complexes on the basis of theoxidation products of maltodextrins. Therefore, an object of the presentinvention are water soluble iron carbohydrate complexes which areobtainable from an aqueous solution of an iron (III) salt and an aqueoussolution of the oxidation product of one or more maltodextrins, using anaqueous hypochlorite solution at an alkaline pH-value of e.g. 8 to 12where, when one maltodextrin is applied, its dextrose equivalent liesbetween 5 and 20, and when a mixture of several maltodextrins isapplied, the dextrose equivalent of the mixture lies between 5 and 20and the dextrose equivalent of each individual maltodextrin contained inthe mixture lies between 2 and 40.

A further object of the present invention is a process for producing theiron carbohydrate complexes according to the invention wherein one ormore maltodextrins are oxidized in an aqueous solution at an alkalinepH-value of e.g. 8 to 12 using an aqueous hypochlorite solution andreacting the obtained solution with an aqueous solution of an iron (III)salt where, when one maltodextrin is applied, its dextrose equivalentlies between 5 and 20, and when a mixture of several maltodextrins isapplied, the dextrose equivalent of the mixture lies between 5 and 20and the dextrose equivalent of each individual maltodextrin contained inthe mixture lies between 2 and 40.

The usable maltodextrins are easily obtainable starting products, andthey are commercially available.

In order to prepare the ligands of the complexes of the invention, themaltodextrins are oxidized in an aqueous solution with a hypochloritesolution. Suitable examples are solutions of alkali hypochlorites suchas a solution of sodium hypochlorite. Commercially available solutionscan be used. The concentration of the hypochlorite solution is, e.g. atleast 13% by weight, preferably in the order of 13 to 16% by weight,calculated as active chlorine. Preferably the solutions are used in suchan amount that about 80 to 100%, preferably about 90% of one aldehydegroup per molecule of maltodextrin is oxidized. In this manner, thereactivity caused by the glucose content of the maltodextrin moleculesis lowered to 20% or less, preferably to 10% or less.

The oxidation is carried out in an alkaline solution, e.g. at a pH of 8to 12, for example 9 to 11. As an example, oxidation can be carried outat temperatures in the order of 15 to 40° C., preferably of 25 to 35° C.The reaction times are, e.g. in the order of 10 minutes to 4 hours, e.g.1 to 1.5 hours.

By this procedure the degree of depolymerisation of the startingmaltodextrins is kept at a minimum. Only theoretically it is assumedthat the oxidation occurs mainly at the terminal aldehyde group (acetalor semiacetal group respectively) of the maltodextrin molecules.

It is also possible to catalyse the oxidation reaction of themaltodextrins. The addition of bromide ions is suitable, e.g. in theform of alkali bromides, for example sodium bromide. The added amount ofbromide is not critical. The amount is kept as low as possible in orderto achieve an end product (Fe-complex) which can easily be purified.Catalytic amounts are sufficient. As stated above, the addition ofbromide is possible, however, not necessary.

Further, it is also possible to use other oxidation systems, such ase.g. the known ternary oxidation system hypochlorite/alkalibromide/2,2,6,6,-tetramethypiperidine-1-oxyl (TEMPO) for the oxidationof the maltodextrins. The process to oxidize maltodextrins catalyticallywith alkali bromides or with the ternary TEMPO system is described e.g.by Thaburet et al in Carbohydrate Research 330 (2001) 21-29, whichmethod can be used for the present invention.

In order to prepare the complexes of the invention the obtained oxidizedmaltodextrins are reacted with an iron (III) salt in an aqueoussolution. In order to do so, the oxidized maltodextrins can be isolatedand redissolved; however, it is also possible to use the obtainedaqueous solutions of the oxidized maltodextrins directly for the furtherreaction with the aqueous iron (III) solutions.

Water soluble salts of inorganic or organic acids, or mixtures thereof,such as halides, e.g. chloride and bromide or sulfates can be used asiron (III) salts. It is preferred to use physiologically acceptablesalts. It is especially preferred to use an aqueous solution of iron(III) chloride.

It has been found that the presence of chloride ions favours theformation of the complexes. The chloride ions can be used in the form ofwater soluble chlorides such as alkali metal chlorides, e.g. sodiumchloride, potassium chloride or ammonium chloride. As stated, the iron(III) is preferably used in the form of the chloride.

For instance, the aqueous solution of the oxidized maltodextrin can bemixed with an aqueous solution of the iron (III) salt in order to carryout the reaction. Here, it is preferred to proceed in a manner so thatduring and immediately after mixing of the oxidized maltodextrin and theiron (III) salt, the pH is strongly acid or so low that no hydrolysis ofthe iron (III) salt occurs, e.g. 2 or less, in order to avoid anundesired precipitation of iron hydroxides. In general, it is notnecessary to add an acid, if iron (III) chloride is used, since aqueoussolutions of iron (III) chloride can be sufficiently acid. Only aftermixing, the pH is raised to values of e.g. in the order of at least 5,for example up to 11, 12, 13 or 14. The pH is preferably raised slowlyor gradually which, for example, can be achieved by first adding a weakbase, for example, up to a pH of about 3, and then neutralizing furtherusing a stronger base. Examples of weak bases are alkali- or alkalineearth-carbonates, bicarbonates, such as sodium and potassium carbonateor bicarbonate, or ammonia. Examples of strong bases are alkali- oralkaline earth-hydroxides such as sodium, potassium, calcium ormagnesium hydroxide.

The reaction can be improved by heating. For example, temperatures inthe order of 15° C. up to boiling point can be used, It is preferred toraise the temperature gradually. Thus, for example, it is possible toheat to about 15 to 70° C. and then raise the temperature gradually upto boiling point.

The reaction times are, for example, in the order of 15 minutes up toseveral hours, e.g. 20 minutes to 4 hours, such as 25 to 70 minutes,e.g. 30 to 60 minutes.

The reaction can be carried out in a weakly acid range, for example, ata pH in the order of 5 to 6. However, it has been found, that it isuseful, but not necessary, to raise the pH during the formation of thecomplexes to higher values of up to 11, 12, 13 or 14. In order tocomplete the reaction, the pH can be lowered then by addition of anacid, for example, to the order of 5 to 6. It is possible to useinorganic or organic acids or mixture thereof, especially hydrogenhalide acids such as hydrogen chloride or aqueous hydrochloric acidrespectively.

As stated above, the formation of the complexes is usually improved byheating. Thus, at the preferred embodiment of the invention, wherein thepH is raised during the reaction to ranges of at least 5 and above up to11 or 14, it is, for instance, possible to work at first at lowertemperatures in the order of 15 to 70° C., such as 40 to 60° C., e.g.about 50° C., whereafter the pH is reduced to values in the order of atleast 5 and the temperature is gradually raised over 50° C. up toboiling point.

The reaction times are in the order of 15 minutes up to several hoursand they can vary depending on the reaction temperature. If the processis carried out with an intermediate pH of more than 5, it is, forexample, possible to work 15 to 70 minutes, e.g. 30 to 60 minutes, atthe enhanced pH, for example at temperatures of up to 70° C., whereafterthe pH is lowered to a range in the order of at least 5 and the reactionis carried out for a further 15 to 70 minutes, e.g. 30 to 60 minutes, attemperatures e.g. up to 70° C., and optionally a further 15 to 70minutes, e.g. 30 to 60 minutes, at higher temperatures up to boilingpoint.

After the reaction the obtained solution can be cooled to e.g. roomtemperature and can optionally be diluted and optionally be filtered.After cooling, the pH can be adjusted to the neutral point or a littlebelow, for example, to values of 5 to 7, by the addition of an acid orbase. It is possible to use e.g. the acids and bases which have beenmentioned for carrying out the reaction. The solutions obtained arepurified and can directly be used for the production of medicaments.However, it is also possible to isolate the iron (III) complexes fromthe solution e.g. by precipitation with an alcohol such as an alkanol,for example, ethanol. Isolation can also be effected by spray-drying.Purification can take place in the usual way, especially in order toremove salts. This can, for example, be carried out by reverse osmosis.It is, for example, possible to carry out the reverse osmosis beforespray-drying or before a direct application in medicaments.

The iron content of the obtained iron (III) carbohydrate complexes is,for example, 10 to 40% weight/weight, especially, 20 to 35%weight/weight. They can easily be dissolved in water. It is possible toprepare neutral aqueous solutions which, e.g. have an iron content of 1%weight/vol. to 20% weight/vol. Such solutions can be sterilisedthermically. The weight average molecular weight mw of the obtainedcomplexes, is, for example, 80 kDa to 400 kDa, preferably 80 kDa to 350kDa, especially preferred up to 300 kDa (measured by gel permeationchromatography, e.g. as described by Geisser et al, in Arzneim.Forsch/Drug Res. 42(II), 12, 1439-1452 (1992), paragraph 2.2.5).

As stated above, it is possible to provide aqueous solutions from thecomplexes of the invention. These solutions are especially useful forparenteral application. However, it is also possible to apply themorally or topically. Contrary to the known parenterally applicable ironpreparations they can be sterilized at high temperatures, e.g. at 121°C. and above, at short contact times of, e.g. 15 minutes, by acquiringF₀≧15. The contact times are correspondingly shorter at highertemperatures. Preparations hitherto known had to be sterilely filtratedand mixed with preservatives, such as benzyl alcohol or phenol. Suchadditives are not necessary in the invention. Hence, it is possible tofill the solutions of the complexes, for example, into ampoules. It is,for example, possible, to fill solutions having a content of 1 to 20% byweight, e.g. 5% by weight, into vessels such as ampoules or phials ofe.g. 2 to 100 ml, e.g., up to 50 ml. The preparation of the parenterallyapplicable solutions can be carried out as known in the art, optionallyusing additives which are normally used for parenteral solutions. Thesolutions can be formulated in such a way that they can be administeredby injection or in the form of an infusion, e.g., in brine solution. Forthe oral or topical application it is possible to formulate preparationswith usual excipients and additives.

Thus, a further object of the invention are aqueous medicaments whichare especially useful for the parenteral, intravenous but alsointramuscular application as well as for the oral or topicalapplication; they are especially useful for the treatment of irondeficiency anaemia. A further object of the invention is also the use ofthe iron (III) carbohydrate complexes according to the invention for thetreatment and prophylaxis of iron deficiency anaemia or the productionof medicaments especially for the parenteral treatment iron deficiencyanaemia. The medicaments can be used in human and veterinary medicine.

The advantages which are achieved with the iron (III) carbohydratecomplexes of the invention are the above-mentioned high sterilisationtemperatures as well as the low toxicity and the reduced danger ofanaphylactic shock. The toxicity of the complexes according to theinvention is very low. The LD₅₀ lies at over 2000 mg Fe/kg, compared tothe LD₅₀ of the known pullulan complexes, which lies at 1400 mg Fe/kg.In view of the high stability of the complexes of the invention, it ispossible to enhance the rates of application as well as the dosages.Thus, it is possible to apply the medicaments of the inventionparenterally in the form of a single dose. Such a single dose is, forexample, 500 to 1000 mg iron; it can be applied, for example, during thecourse of one hour. A further advantage lies in the high degree ofavailability of the maltodextrins used as starting products, which are,e.g., commercially available additives in the food processing industry.

In the present description, as well as in the following examples, thedextrose equivalents are measured gravimetrically. In order to do so,the maltodextrins are reacted in a boiling aqueous solution withFehling's solution. The reaction is carried out quantitatively, i.e.until the Fehling's solution is no longer discoloured. The precipitatedcopper (I) oxide is dried at 105° C. until a constant weight is achievedand measured gravimetrically. The glucose content (dextrose equivalent)is calculated from the obtained results as % weight/weight of themaltodextrin dry substance. It is, for example, possible to use thefollowing solutions: 25 ml Fehling's solution I, mixed with 25 mlFehling's solution II; 10 ml aqueous maltodextrin solution (10% mol/vol)(Fehling's solution I: 34.6 g copper (II) sulfate dissolved in 500 mlwater; Fehling's solution II: 173 g potassium sodium tartrate and 50 gsodium hydroxide dissolved in 400 ml water).

EXAMPLE 1

100 g maltodextrin (9.6 dextrose equivalent measured gravimetrically)are dissolved by stirring in 300 ml water at 25° C. and oxidized byaddition of 30 g sodium hypochlorite solution (13 to 16 weight percentactive chlorine) at pH 10.

At first, the oxidized maltodextrin solution and then 554 g sodiumcarbonate solution (17.3% weight/weight) are added at room temperatureto 352 g of a stirred iron (III) chloride solution (12% weight by weightFe).

Then, the pH is adjusted to 11 by addition of sodium hydroxide and thesolution is heated to 50° C. and kept at 50° C. for 30 minutes. Then,acidification to a pH of 5 to 6 is effected by addition of hydrochloricacid, the solution is kept at 50° C. for a further 30 minutes and thenheated to 97-98° C. and the temperature is kept for 30 minutes at thisrange. After cooling the solution to room temperature, the pH isadjusted to 6-7 by the addition of sodium hydroxide.

The solution is then-filtered through a sterilisation filter and thenexamined for sediments. Thereafter, the complex is isolated byprecipitation with ethanol in a range of 1:0.85 and then dried in vacuumat 50° C.

The yield is 125 g (corresponding to 87% of the theoretical value) of abrown amorphic powder having an iron content of 29,3% weight/weight(measured complexometrically).

Molecular weight mw 271 kDa.

EXAMPLE 2

200 g maltodextrin (9.6 dextrose equivalent measured gravimetrically)are dissolved by stirring in 300 ml water at 25° C. and oxidized byaddition of 30 g sodium hypochlorite solution (13 to 16 weight percentactive chlorine) at pH 10.

At first the oxidized maltodextrin solution and then 554 g sodiumcarbonate solution (17.3% weight/weight) are added at room temperatureto 352 g of a stirred iron (III) chloride solution (12% weight by weightFe).

Then the pH is adjusted to 11 by addition of sodium hydroxide and thesolution is heated to 50° C. and kept for 30 minutes at 50° C. Then,acidification to a pH of 5 to 6 is effected by addition of hydrochloricacid, the solution is kept at 50° C. for a further 30 minutes and thenheated to 97-98° C. and the temperature is kept for 30 minutes at thisrange. After cooling the solution to room temperature the pH is adjustedto 6-7 by the addition of sodium hydroxide.

The solution is then filtered through a sterilisation filter and thenexamined for sediments. Thereafter, the complex is isolated byprecipitation with ethanol in a range of 1:0.85 and then dried in vacuumat 50° C.

The yield is 123 g (corresponding to 65% of the theoretical value) of abrown amorphic powder having an iron content of 22.5% weight/weight(measured complexometrically).

Molecular weight mw 141 kDa.

EXAMPLE 3

100 g maltodextrin (9.6 dextrose equivalent measured gravimetrically)are dissolved by stirring in 300 ml water at 25° C. and oxidized byaddition of 30 g sodium hypochlorite solution (13 to 16 weight percentactive chlorine) and 0.7 g sodium bromide at pH 10.

At first the oxidized maltodextrin solution and then 554 g sodiumcarbonate solution (17.3% weight/weight) are added at room temperatureto 352 g of a stirred iron (III) chloride solution (12% weight by weightFe).

Then the pH is adjusted to 6.5 by addition of sodium hydroxide and thesolution is heated to 50° C. and kept for 60 minutes at 50° C. Then,acidification to a pH of 5 to 6 is effected by addition of hydrochloricacid, the solution is kept at 50° C. for a further 30 minutes and thenheated to 97-98° C. and the temperature is kept for 30 minutes at thisrange. After cooling the solution to room temperature the pH is adjustedto 6-7 by the addition of sodium hydroxide.

The solution is then filtered through a sterilisation filter and thenexamined for sediments. Thereafter, the complex is isolated byprecipitation with ethanol in a range of 1:0.85 and then dried in vacuumat 50° C.

The yield is 139 g (corresponding to 88% of the theoretical value) of abrown amorphic powder having an iron content of 26.8% weight/weight(measured complexometrically).

Molecular weight mw 140 kDa.

EXAMPLE 4

A mixture of 45 g maltodextrin (6.6 dextrose equivalent measuredgravimetrically) and 45 g maltodextrin (14.0 dextrose equivalentmeasured gravimetrically) is dissolved by stirring in 300 ml water at25° C. and oxidized by addition of 25 g sodium hypochlorite solution (13to 16 weight percent active chlorine) and 0.6 g sodium bromide at pH 10.

At first the oxidized maltodextrin solution and then 554 g sodiumcarbonate solution (17.3% weight/weight) are added at room temperatureto 352 g of a stirred iron (III) chloride solution (12% weight by weightFe).

Then the pH is adjusted to 11 by addition of sodium hydroxide and thesolution is heated to 50° C. and kept for 30 minutes at 50° C. Then,acidification to a pH of 5 to 6 is effected by addition of hydrochloricacid, the solution is kept at 50° C. for a further 30 minutes and thenheated to 97-98° C. and the temperature is kept for 30 minutes at thisrange. After cooling the solution to room temperature the pH is adjustedto 6-7 by the addition of sodium hydroxide.

The solution is then filtered through a sterilisation filter and thenexamined for sediments. Thereafter, the complex is isolated byprecipitation with ethanol in a range of 1:0.85 and then dried in vacuumat 50° C.

The yield is 143 g (corresponding to 90% of the theoretical value) of abrown amorphic powder having an iron content of 26.5% weight/weight(measured complexometrically).

Molecular weight mw 189 kDa.

EXAMPLE 5

90 g maltodextrin (14.0 dextrose equivalent measured gravimetrically)are dissolved by stirring in 300 ml water at 25° C. and oxidized byaddition of 35 g sodium hypochlorite solution (13 to 16 weight percentactive chlorine) and 0.6 g sodium bromide at pH 10.

At first, the oxidized maltodextrin solution and then 554 g sodiumcarbonate solution (17.3% weight/weight) are added at room temperatureto 352 g of a stirred iron (III) chloride solution (12% weight by weightFe).

Then the pH is adjusted to 11 by addition of sodium hydroxide and thesolution is heated to 50° C. and kept for 30 minutes at 50° C. Then,acidification to a pH of 5 to 6 is effected by addition of hydrochloricacid, the solution is kept at 50° C. for a further 30 minutes and thenheated to 97-98° C. and the temperature is kept for 30 minutes at thisrange. After cooling the solution to room temperature the pH is adjustedto 6-7 by the addition of sodium hydroxide.

The solution is then filtered through a sterilisation filter and thenexamined for sediments. Thereafter, the complex is isolated byprecipitation with ethanol in a range of 1:0.85 and then dried in vacuumat 50° C.

The yield is 131 g (corresponding to 93% of the theoretical value) of abrown amorphic powder having an iron content of 29.9% weight/weight(measured complexometrically).

Molecular weight mw 118 kDa.

EXAMPLE 6

A mixture of 45 g maltodextrin (5.4 dextrose equivalent measuredgravimetrically) and 45 g maltodextrin (18.1 dextrose equivalentmeasured gravimetrically) is dissolved by stirring in 300 ml water at25° C. and oxidized by addition of 31 g sodium hypochlorite solution (13to 16 weight percent active chlorine) and 0.7 g sodium bromide at pH 10.

At first the oxidized maltodextrin solution and then 554 g sodiumcarbonate solution (17.3% weight/weight) are added at room temperatureto 352 g of a stirred iron (III) chloride solution (12% weight by weightFe).

Then the pH is adjusted to 11 by addition of sodium hydroxide and thesolution is heated to 50° C. and kept for 30 minutes at 50° C. Then,acidification to a pH of 5 to 6 is effected by addition of hydrochloricacid, the solution is kept at 50° C. for a further 30 minutes and thenheated to 97-98° C. and the temperature is kept for 30 minutes at thisrange. After cooling the solution to room temperature the pH is adjustedto 6-7 by the addition of sodium hydroxide.

The solution is then filtered through a sterilisation filter and thenexamined for sediments. Thereafter, the complex is isolated byprecipitation with ethanol in a range of 1:0.85 and then dried in vacuumat 50° C.

The yield is 134 g (corresponding to 88% of the theoretical value) of abrown amorphic powder having an iron content of 27.9% weight/weight(measured complexometrically).

Molecular weight mw 178 kDa.

EXAMPLE 7

100 g maltodextrin (9.6 dextrose equivalent measured gravimetrically)are dissolved by stirring in 300 ml water at 25° C. and oxidized byaddition of 29 g sodium hypochlorite solution (13 to 16 weight percentactive chlorine) and 0.7 g sodium bromide at pH 10.

At first the oxidized maltodextrin solution and then 554 g sodiumcarbonate solution (17.3% weight/weight) are added at room temperatureto 352 g of a stirred iron (III) chloride solution (12% weight by weightFe).

Then the pH is adjusted to 11 by addition of sodium hydroxide and thesolution is heated to 50° C. and kept for 30 minutes at 50° C. Then,acidification to a pH of 5 to 6 is effected by addition of hydrochloricacid, the solution is kept at 50° C. for a further 70 minutes. Aftercooling the solution to room temperature the pH is adjusted to 6-7 bythe addition of sodium hydroxide.

The solution is then filtered through a sterilisation filter and thenexamined for sediments. Thereafter, the complex is isolated byprecipitation with ethanol in a range of 1:0.85 and then dried in vacuumat 50° C.

The yield is 155 g (corresponding to 90% of the theoretical value) of abrown amorphic powder having an iron content of 24.5% weight/weight(measured complexometrically).

Molecular weight mw 137 kDa.

EXAMPLE 8

126 g maltodextrin (6.6 dextrose equivalent measured gravimetrically)are dissolved by stirring in 300 ml water at 25° C. and oxidized byaddition of 24 g sodium hypochlorite solution (13 to 16 weight percentactive chlorine) and 0.7 g sodium bromide at pH 10.

At first the oxidized maltodextrin solution and then 554 g sodiumcarbonate solution (17.3% weight/weight) are added at room temperatureto 352 g of a stirred iron (III) chloride solution (12% weight by weightFe).

Then the pH is adjusted to 11 by addition of sodium hydroxide and thesolution is heated to 50° C. and kept for 30 minutes at 50° C. Then,acidification to a pH of 5 to 6 is effected by addition of hydrochloricacid, the solution is kept at 50° C. for a further 70 minutes. Aftercooling the solution to room temperature the pH is adjusted to 6-7 bythe addition of sodium hydroxide.

The solution is then filtered through a sterilisation filter and thenexamined for sediments. Thereafter, the complex is isolated byprecipitation with ethanol in a range of 1:0.85 and then dried in vacuumat 50° C.

The yield is 171 g (corresponding to 86% of the theoretical value) of abrown amorphic powder having an iron content of 21.35% weight/weight(measured complexometrically).

Molecular weight mw 170 kDa.

Comparative Test

In the following the characteristics of the iron carbohydrate complexesare compared with a commercially available iron sucrose complex. It canbe seen that the iron content can be enhanced, the thermal treatment canbe carried out at higher temperatures and the toxicity (LD₅₀) can belowered in accordance with the invention.

According to the Iron hydroxide/sucrose invention complex Fe content [%]5.0 2.0 pH 5-7  10.5-11.0 mw [kDa]¹⁾ 80-350 34-54 Thermal treatment 121°C./15′ 100° C./35′ LD₅₀ i.v., w.m. [mg >2000 >200 Fe/kg body weight]

1. A water soluble iron carbohydrate complex having a weight averagemolecular weight (Mw) of 80,000 to 400,000, comprising the reactionproduct of: (a) an aqueous solution of an iron (III) salt and (b) anaqueous solution of the oxidation product of (i) at least onemaltodextrin and (ii) an aqueous hypochlorite solution at an alkalinepH, wherein, when one maltodextrin is present, the maltodextrin has adextrose equivalent of between 5 and 20, and wherein, when a mixture ofmore than one maltodextrin is present, the dextrose equivalent of eachindividual maltodextrin is between 2 and 40, and the dextrose equivalentof the mixture is between 5 and
 20. 2. A medicament comprising anaqueous solution of the iron carbohydrate complex of claim
 1. 3. Themedicament of claim 2, wherein the medicament is formulated forparenteral or oral application.
 4. The water soluble iron carbohydratecomplex of claim 1, wherein the iron carbohydrate complex has a weightaverage molecular weight (Mw) of 80,000 to 350,000.
 5. The water solubleiron carbohydrate complex of claim 1, wherein the iron carbohydratecomplex has a weight average molecular weight (Mw) of 80,000 to 300,000.6. A process for producing a water soluble iron carbohydrate complexhaving a weight average molecular weight (Mw) of 80,000 to 400,000,comprising the steps of: (a) oxidizing at least one maltodextrin in anaqueous solution at an alkaline pH with an aqueous hypochlorite solutionto form an oxidized maltodextrin solution, and (b) contacting theoxidized maltodextrin solution with an aqueous solution of an iron (III)salt, wherein, when one maltodextrin is present, the maltodextrin has adextrose equivalent of between 5 and 20, and wherein, when a mixture ofmore than one maltodextrin is present, the dextrose equivalent of eachindividual maltodextrin is between 2 and 40, and the dextrose equivalentof the mixture is between 5 and
 20. 7. The process of claim 6, whereinthe iron (III) salt is iron (III) chloride.
 8. The process of claim 7,wherein step (b) is carried out at a pH of 2 or less to form a finalsolution, and the process further comprises (c) raising the pH of thefinal solution to a value in the range of 5 to
 12. 9. The process ofclaim 7, wherein step (b) is carried out at a temperature of from 15° C.to the boiling point for 15 minutes up to several hours.
 10. The processof claim 6, wherein step (b) is carried out at a pH of 2 or less to forma final solution, and the process further comprises (c) raising the pHof the final solution to a value in the range of 5 to
 12. 11. Theprocess of claim 10, wherein step (b) is carried out at a temperature offrom 15° C. to the boiling point for 15 minutes up to several hours. 12.The process of claim 6, wherein step (a) is carried out in the presenceof bromide ions.
 13. The process of claim 12, wherein step (b) iscarried out at a temperature of from 15° C. to the boiling point for 15minutes up to several hours.
 14. The process of claim 12, wherein theiron (III) salt is iron (III) chloride.
 15. The process of claim 14,wherein step (b) is carried out at a pH of 2 or less to form a finalsolution, and the process further comprises (c) raising the pH of thefinal solution to a value in the range of 5 to
 12. 16. The process ofclaim 12, wherein step (b) is carried out at a pH of 2 or less to form afinal solution, and the process further comprises (c) raising the pH ofthe final solution to a value in the range of 5 to
 12. 17. The processof claim 6, wherein step (b) is carried out at a temperature of from 40°C. to 60° C.
 18. The process of claim 6, wherein step (b) is carried outat a temperature of from 50° C. to the solution boiling point.
 19. Aprocess for producing a water soluble iron carbohydrate complex having aweight average molecular weight (Mw) of 80,000 to 400,000, comprisingthe steps of: (a) oxidizing at least one maltodextrin in an aqueoussolution at a pH in the range of 8 to 12 and a temperature in the rangeof 15 to 40° C., for 10 minutes to 4 hours with an aqueous hypochloritesolution to form an oxidized maltodextrin solution, (b) contacting theoxidized maltodextrin solution with an aqueous solution of an iron (III)salt and (c) raising the pH of the oxidized maltodextrin solution andiron (III) salt to a value in the range of 5 to 14, wherein, when onemaltodextrin is present, the maltodextrin has a dextrose equivalent ofbetween 5 and 20, and wherein, when a mixture of more than onemaltodextrin is present, the dextrose equivalent of each individualmaltodextrin is between 2 and 40, and the dextrose equivalent of themixture is between 5 and
 20. 20. The process of claim 19, wherein atleast one of the following steps are carried out: (1) step (a) iscarried out at a pH in the range of 9 to 11; (2) the temperature atwhich step (a) is carried out is in the range of 25 to 35° C.; (3) step(a) is carried out for 1 to 1.5 hours.
 21. The process of claim 19,wherein (b) is carried out at a pH of 2 or less.
 22. The process ofclaim 19, wherein in (c), the pH is raised to a value in the range of 11to
 14. 23. The process of claim 19, further comprising after (c), (d)reducing the pH of the solution to a value in the range of 5 to
 6. 24.The process of claim 23, wherein, simultaneous with (c), the solutiontemperature is or maintained in, the range of 15 to 70° C.
 25. Theprocess of claim 23, wherein simultaneous with (d), the solutiontemperature, if it is not already at least 50° C., is raised to 50° C.,followed by gradually raising the temperature to the solution boilingpoint.
 26. The process of claim 25, further comprising after (d), (e)cooling the solution to room temperature.
 27. The process of claim 26,further comprising after (e), (f) adjusting the pH to a value in therange of 6 to 7.